THE EFFICACY OF LAMIVUDINE TREATMENT IN NAIVE CHRONIC HEPATITIS B PATIENTS

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1 Acta Medica Mediterranea, 2016, 32: 663 THE EFFICACY OF LAMIVUDINE TREATMENT IN NAIVE CHRONIC HEPATITIS B PATIENTS AYHAN BALKAN, SEZGIN BARUTÇU, RAMAZAN ERDEM, BUĞRA TOLGA KONDUK, ABDULLAH EMRE YILDIRIM, MURAT TANER GÜLŞEN Gaziante University, Faculty of Medicine, Deartment of Gastroenterology, Gaziante, Turkey ABSTRACT Introduction: According to our national health care system revious guidelines, lamivudine (LAM) or telbivudine treatment should be initiated in the naive chronic heatitis B (CHB) atients with low viral load. We aimed to investigate the success of LAM treatment in one year eriod. Materials and methods: We retrosectively recruited 125 naive CHB atients on LAM theray. We recorded biosy results, demograhic, biochemical, serological and virological values at baseline and 3 rd, 6 th and 12 th months of treatment. Virological resonse was defined as undetectable heatitis B virus (HBV) DNA (<20 IU/mL). Results: Of atients, 81 were male (65%), and the mean age was 42 ± 13. Mean histological activity index (HAI) was 4.55 ± 2.16, and fibrosis was 2.65 ± 0.90 in 114 atients who had biosy results. The initial mean HBV DNA level was IU/mL. Seroconversion was observed in only 3 (18.75%) of 16 HBeAg (+) atients. While baseline median ALT value was 36 U/L, following values were 28 U/L, 25 U/L and 24 U/L, resectively. HBV DNA significantly and gradually decreased with LAM treatment and it was finally determined to be negative in 80% of the atients in the 12 th month. Conclusion: LAM treatment for naive CHB atients continues to be effective for the first 6 th months, and if continued to be treated until 12 th month, this efficiency can increase. However, it should be ket in mind that any atient with ositive HBV DNA are under risk of HBV related comlications. Key words:efficacy, lamivudine, chronic heatitis B. DOI: / _2016_3_72 Received June 30, 2015; Acceted January 02, 2016 Introduction Chronic heatitis B (CHB) is today s imortant health roblem concerning 400 millions of eole in the world. According to the World Health Organization, one-third of the world oulation is infected with heatitis B virus (HBV), and 5% of them are chronically ill. About one-fourth of these chronic atients rogress to heatic cirrhosis and liver cancer, which are the fatal liver diseases. As a consequence, one million eole a year ass away from HBV (1,2). Fortunately, it is a treatable disease, and the treatment includes two different otions: egylated interferons and oral antiviral agents. Advantages of the egylated interferons include the lack of resistance, ossibility to terminate the treatment, and a higher rate of HBsAg loss; however their low tolerability, and existence of side-effects like anemia, leukoenia, thrombocytoenia, skin reactions and deression, limit their use (3). Oral antiviral agents are classified in two grous, as nucleoside analogs [lamivudine (LAM), telbivudine, emtricitabine, and entecavir] and nucleotide analogs (adefovir and tenofovir). These drugs lower the HBV DNA raidly; however develoment of resistance is still a great roblem in these grous of drugs (4-7). Resistance and mutant strains still exist as great roblems esecially in the old generation oral antiviral agents (LAM, adefovir or telbivudine

2 664 Ayhan Balkan, Sezgin Barutçu et Al (LdT)). In the treatment of CHB, YMDD mutation in the HBV olymerase gene roduces resistance to LAM. N236T and A181V resistances to adefovir diivoxile have begun to be reorted; however in most of these strains in vivo and in vitro LAM sensitivities still exist (8). In the recent years, Antiviral Drug-Associated Potential Vaccine Escae Mutant (ADAPVEM) has been defined that develos due to HBV ol/s gene coincidence (9,10). HBV vaccine escae mutations may also lead to false negativities in the HBsAg diagnostic tests, and insufficient rotection by the heatitis B immunoglobulin (HBIg) (10-12). LAM is no longer included in the drug guides for CHB treatment in the world. It has been used in our country for many years because of the Declaration for Health Alication (DHA), and thus considerable exerience is gained. In the resent study, we aimed to reveal the efficacy of LAM in a eriod of one-year treatment, in the atients with CHB who were administered LAM theray in the direction of DHA. Materials and methods Study design 125 atients with naive CHB that are recorded in our heatology clinic, were included in the study; the cases had been taking LAM treatment 100 mg/day, for 12 months. Biochemical, serological and virological test results of these atients obtained before treatment, and in the 3 rd, 6 th and 12 th months of treatment were investigated retrosectively. Demograhic data and results of re-treatment liver biosies were also noted. A value of HBV DNA < 20 IU/mL was acceted to be negative. The study was carried out in accordance with the rinciles of the revised 2013 version of the Declaration of Helsinki of 1975, with the aroval numbered /159 of University of Gaziante Faculty of Medicine Clinical Research Ethics Committee. Patients 18 -year old atients and those above 18 were included in the study. All atients were evaluated for HBsAg, HBeAg, anti-hbe, anti-hdv, anti- HCV, and anti-hiv, using enzyme linked immunosorbent assay (ELISA) method. HBV DNA test was erformed using quantitative olymerase chain reaction method (Amlicor HBV Monitor test, Roche Diagnostic Systems Inc., Branchburg, NJ) (sensitivity 20 IU/ ml). HBsAg ositivity for more than six months was considered as CHB infection. Patients reviously taking antiviral agents or egylated interferon, cases with cirrhosis, ones with heatitis delta virus (HDV), heatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection, and atients associated with an autoimmune liver disease or renal failure, were excluded from the study. Liver histology Of the 125 atients included in the study, 114 existed with liver biosies. In the remaining 11 atients, treatment was started without administering liver biosy. Histoathological examinations were carried out according to the Ishak scoring system (13). Statistical analysis Statistical analyses were erformed using licenced Statistical Package for the Social Sciences (SPSS) software (version 15.0, SPSS Inc., Chicago, IL, USA). Chi-square test was used for evaluating the statistical significance of the relation between two variables. When analyzing by the Chi-square test, Fisher s exact correction test was also used if needed. A value < or=0.05 was acceted to be significant. Results Of the 125 atients included in the study, 81 were males (65%); the mean age of the cases was ± years. Median value of the histological activity index (HAI) in the 114 cases who underwent liver biosy, was found to be 7; the median for the existence of fibrosis was 3.5. Demograhic and clinical characteristics of the atients, and the roerties of the liver histology, are resented in Table 1. The initial mean value of the HBV DNA was 5.52 x 106 IU/mL. With the LAM treatment, DNA load was found to decrease by 2-log every 3 months, till the 6 th month. Of the 16 atients with HBeAg ositivity, only 3 (18.75%) existed with seroconversion. Basal median value of ALT was found to be 36 U/L (5-33 U/L); the median values of ALT in the 3 rd, 6 th and 12 th months of treatment were in normal ranges (Table 2). HBV DNA significantly and gradually decreased in the analyses reeated once every three months, and it was finally determined to be negative in 80% of the atients in the 12 th month (Table 3).

3 The efficacy of lamivudine treatment in naive chronic heatitis B atients 665 Patient characteristics Age (years), Patient grous (n=125) Baseline 3 rd month 6 th month 12 th month ALT (median, U/L) Median 58 Range Gender, Male (%) 65 ALT, U/L Median 36 Range Total bilirubin, mg/dl Median 0.78 Range Albumin, g/dl Median 4.74 WBC, 10³/µL Median Hemoglobin, g/dl Median Platelet, 10³/µL Median 137 INR HBeAg (+) HBeAg (-) HBV-DNA (mean, IU/mL) 5.52x x x Table 2: ALT, Serological and Virological Values of CHB atients Prior to and During One Year Period of Treatment. ALT, alanine aminotransferase; CHB, chronic heatitis B; HBV, heatitis B virus Baseline rd month (66%) 0,0001 a 6 th month (68%) b 12 th month (80%) 0.03 c Table 3: Virological resonse rates in CHB atients by months. CHB, chronic heatitis B; HBV, heatitis B virus Median 1 AFP, ng/ml Median 5.05 Baseline Range HBV DNA, 10³ IU/mL Median 30 Range Histological activity index Median 7 Range Fibrosis 13-Jan Median 3.5 Table 1: Demograhic and Clinical Characteristics of the Patients. AFP, alha-fetorotein; ALT, alanine aminotransferase; HBV, heatitis B virus; INR, international normalized ratio; WBC, white blood cell. When the atients were evaluated by searating to two grous as HBeAg ositive or negative, 86% of the HBeAg(-) cases were found to be negative for HBV DNA at the end of the 12 th month, with the LAM treatment; HBV DNA was negative in 56% of HBeAg(+) atients at the end of this eriod (Tables 4 and 5). 3 rd month (71%) a 6 th month (72%) b 12 th month (86%) c Table 4: Virological resonse rates in HBe Ag (-) CHB atients by months. CHB, chronic heatitis B; HBV, heatitis B virus Baseline 16-3 rd month 9 7 (44%) a 6 th month 8 8 (50%) b 12 th month 7 9 (56%) 1.00 c Table 5: Virological resonse rates in HBe Ag (+) CHB atients by months.

4 666 Ayhan Balkan, Sezgin Barutçu et Al Discussion LAM is the first nucleoside analog that was confirmed for the treatment of CHB. It is well-tolerated by the atients, and it has less number of side-effects limiting its use. It revents virus relication by blocking the reverse transcritase enzyme. Heatic enzyme levels are normalized, and serum HBV DNA load decreases in the atients with CHB who are treated with LAM (1). However, disease may relase a short eriod after the treatment is discontinued, and drug resistance develos during treatment, that are the unwanted negative consequences of treatment with LAM (14,15). Results of 731 studies including atients with CHB who are ositive for HBeAg, and exist with ersistent or intermittent increases in transaminases, were evaluated; rate of HBeAg seroconversion was found to change between 16% and 18% in the cases treated with LAM for one year, and this rate was 3- to 4-fold better when comared to the untreated controls. Rate of HBeAg seroconversion increases linearly with the increase in duration of treatment, and it reaches a level of about 50% in 5 years (16). In our study, 3 of the 16 atients (18.75%) existed with HBeAg seroconversion at the end of first year. There are studies reorting that LAM causes histological imrovement in the liver. In some studies, necroinflammation was determined to regress by 2 oints or more in 49% to 56% of the atients receiving LAM treatment (16). Because the resent study is a retrosective one, histological imrovement could not be roven in the atients by control biosies. As also mentioned above, the most imortant roblem in the treatment of CHB with LAM, is the develoment of resistance to drug, that linearly increases with the increase in the duration of treatment. Mutations begin to exist 6 months after the initiation of treatment with LAM, and mutation rates continue to increase as duration of treatment is rolonged. In the revious studies, resistance to LAM was reorted to increase related with the duration of treatment, as follows: rate of resistance to LAM 22% in the 1 st year, 38% in the 2 nd year, 53% in the 3 rd year, 66% in the 4 th year. The disease may be activated due to the resistance to drug, and the atient may exist with the worsening biochemical, viral and histological signs. This condition may reverse the disease to the re-treatment state, and even to a worse level than that (17). In the studies conducted in our country, HBsAg ositivity has been determined to be about 4%, and this rate decreased slightly with the start of routine vaccination, comared to the revious years (18). Our atients with CHB have been treated with LAM by considering the rules of administrative health alications in our country, and the rate of HBV DNA negativity reached a level of 80% at the end of the 1st year; the treatment was therefore determined to be efficient. This treatment has maintained a significant rate of HBV DNA negativity; however, we now know that a 20% of atient oulation that could not be treated, confronted the roblem of ADAPVEM. Drug resistance mutations that develo during the treatment of CHB with nucleoside analogs, can affect the structure and functions of the HBsAg. Mutations develoing in and around the major neutralization coil, which is known as the a determinant of the HBsAg rotein, lead to decreased resonse to heatitis B vaccination (9,10). A study conducted in our country has roven that ADAPVEMs may develo in all clinical hases of CHB, and ADAPVEM develoment redominates in the treatments with NA (24%), comared to the naive individuals (0.7%) (19). According to the revious DHA in our country, nucleoside analogs treatment could be initiated only with LAM or LdT in the atients with CHB, existing with a HBV DNA level of <10 7 IU/mL. In countries where LAM or LdT treatment is common, it may be imortant for the ublic health to followu the atients attentively for the existence of ADAPVEM. In another study conducted with LAM treatment, 61 atients with HBeAg ositivity were treated with LAM for 24 months; in this study, advanced age was found to be the only factor that causes existence of viral breakthrough, and gender, re-treatment levels of ALT and HBV DNA, HBeAg seroconversion time and re-treatment HAI were determined not to affect it (20). In our study, virological resonse rates to 12-month treatment with LAM in the atients with CHB, were found to be higher in the cases with HBeAg negativity, comared to those existing with HBeAg ositivity; these results were in accordance with the literature (3). It is also claimed that LAM is an antiviral agent that can be safely used in the secial grous of atients diagnosed as CHB (3 rd trimester of regnancy, atients with comensated and decomensated cirrhosis, and atients that would receive immunosuressive drug treatment or cytotoxic

5 The efficacy of lamivudine treatment in naive chronic heatitis B atients 667 chemotheray or monoclonal antibody treatment) (3). Our study did not include these cases, since they were considered in the criteria for being excluded. As a conclusion, LAM treatment leads to HBV DNA negativity in a high rate in the 6th month, in the naive CHB atients. This rate even increases more in the 12 th month, if the treatment is continued. However, in the resence of antiviral agents that are novel, more otent and with roerties of more delayed develoment of resistance, it may carry risk to start the treatment with LAM regarding the comlications of HBV. However, in the countries that aly national health olicies integrated with the economy, LAM still exists as one of the treatment otions to be used in the first 6 months. References 1) Lai CL, Ratziu V, Yuen MF, Poynard T. Viral heatitis B. Lancet 2003; 362: ) Allen MI, Deslauriers M, Andrews CW, Tiles GA, Walters KA, et al. Identification and Characterization of mutations in heatitis B virus resistant to lamivudine. Heatology 1998; 27: ) EASL clinical ractice guidelines: Management of chronic heatitis B virus infection. Journal of heatology 2012; 57: ) Hadziyannis SJ, Paatheodoridis GV, Dimou E, Laras A, Paaioannou C. Efficacy of long-term lamivudine monotheray in atients with heatitis B e antigen-negative chronic heatitis B. Heatology 2000; 32: ) Hadziyannis SJ, Tassooulos NC, Heathcote EJ, Chang TT, Kitis G, et al. Long-term theray with adefovir diivoxil for HBeAg-negative chronic heatitis B for u to 5 years. Gastroenterology 2006; 131: ) Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, et al. Telbivudine versus lamivudine in atients with chronic heatitis B. N Engl J Med 2007; 357: ) Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, et al. 2-Year GLOBE trial results: telbivudine Is suerior to lamivudine in atients with chronic heatitis B. Gastroenterology 2009; 136: ) EASL International Consensus Conference on Heatitis B Setember, 2002: Geneva, Switzerland. Consensus statement (short version). J Heatol 2003; 38: ) Clements CJ, Coghlan B, Creati M, Locarnini S, Tedder RS, et al. Global control of heatitis B virus: does treatment-induced antigenic change affect immunization? Bull World Health Organ 2010; 88(1): ) Torresi J. The virological and clinical significance of mutations in the overlaing enveloe and olymerase genes of heatitis B virus. J Clin Virol 2002; 25(2): ) Avellon A, Echevarria JM. Frequency of heatitis B virus a determinant variants in unselected Sanish chronic carriers. J Med Virol 2006; 78(1): ) Teo CG, Locarnini SA. Potential threat of drug-resistant and vaccine-escae HBV mutants to ublic health. Antivir Ther 2010; 15(3 Pt B): ) Ishak K, Batista A, Bianchi L, Callea F, De Groote J, et al. Histological grading and staging of chronic heatitis. J Heatol 1995; 22: ) Suzuki F, Suzuki Y, Tsubota A, Akuta N, Someya T, et al. Mutations of olymerase, recore and core romoter gene in heatitis B virus during 5-year lamivudine theray. J Heatol 2002; 37: ) Akuta N, Tsubota A, Suzuki F, Suzuki Y, Hosaka T, et al. Long-term rognosis by lamivudine monotheray for severe acute exacerbation in chronic heatitis B infection: emergence of YMDD motif mutant and risk of breakthrough heatitis - an oen-cohort study. J Heatol 2003; 38: ) Lok ASF, McMahon BJ. Chronic heatitis B. Heatology 2007; 45: ) Fournier C, Zoulim F. Antiviral theray of chronic heatitis B: revention of drug resistance. Clin Liver Dis 2007; 11: ) Balık İ, Tosun S, Tabak F, Örmeci N, Saltoğlu N, et al. Ülkemizde HBsAg ve Anti-HCV durumu. 10. Ulusal Viral Heatit Kongresi Antalya. Turkish. 19) Sayan M, Akhan SC. Antiviral drug-associated otential vaccine-escae HBV mutants in Turkish atients with chronic heatitis B. Int J Infect Dis 2011; 15(10): ) Ryu SH, Chung YH, Choi MH, Kim JA, Shin JW, et al. Long-term additional lamivudine theray enhances durability of lamivudine-induced HBeAg loss: a rosective study. J Heatol 2003; 39: Acknowledgement: This study was resented at the 24 th Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2015), March 12-15, 2015, İstanbul, Turkey. We thank the study investigators, coordinators, nurses, atients and their families for their contributions. Ethical aroval The study was carried out in accordance with the rinciles of the revised 2013 version of the Declaration of Helsinki of 1975, with the aroval numbered /159 of University of Gaziante Faculty of Medicine Clinical Research Ethics Committee. Corresonding author AYHAN BALKAN Assistant Professor Doctor, Deartment of Gastroenterology, Gaziante University, Faculty of Medicine, Üniversite Bulvarı Şehitkamil, Gaziante, (Turkey)